Poulain, P., Denier, W., Douma, J., Hoerauf, K., Samija, M., Sopata, M., & Wolfram, G. (2008). Efficacy and safety of transdermal buprenorphine: A randomized, placebo-controlled trial in 289 patients with severe cancer pain. Journal of Pain and Symptom Management, 36(2), 117–125.

To investigate the analgesic efficacy and safety of a transdermal buprenorphine patch used by patients with chronic severe cancer pain

Eligible patients participated in an open-label two-week phase in which they stopped drug therapy with previously prescribed analgesics. In this phase patients started drug therapy that consisted of a 70 mcg buprenorphine (BUP) transdermal (TDS) patch applied every three days. Pain intensity scores and intake of rescue medication, sublingual BUP, indicated whether a patient responded to BUP TDS. At the end of two weeks, patients who responded to BUP TDS were assigned to the BUP TDS group or the placebo group for a two-week maintenance phase. Patients used rescue medication for breakthrough pain as needed. BUP and placebo patches were identical in appearance and adhesive properties. Twice daily patients reported current pain on a 10-point scale. Authors evaluated the amount of BUP rescue medication taken and patients’ global satisfaction with treatment. At each visit the patient was asked to report any new adverse event.

• Initially, 289 patients entered the trial. The analyzed sample was composed of 188 patients.
• Mean patient age was 63 years. Age range was 29–90 years.
• Of all patients, 42.9% were female and 57.1% were male.
• Of all patients, 73% had metastatic disease. The most frequent metastases were to bone, liver, and lung. More than 30% of patients were also receiving corticosteroids and/or benzodiazepines. Overall, 35% of patients were receiving adjuvant chemotherapy, 18% were receiving hormone treatment, and 9% had had radiotherapy. Eligible patients had received insufficient pain relief from opioid regimens used before the study. Patients were receiving single or combination opioid therapy. Use of adjuvant analgesics—such as tricyclic antidepressants, benzodiazepines, anticonvulsants, muscle relaxants, or corticosteroids—was allowed if doses were stable.

• Multisite
• Twenty-six cancer centers in Austria, Belgium, Croatia, France, Poland, and the Netherlands

Randomized double-blind, placebo-controlled trial following an initial two-week open-label phase

• Ten-point numeric rating scale, to measure pain
• Five-point Likert scale, to measure patients' global satisfaction with treatment

• Of the 289 subjects entered, 32% discontinued BUP TDS treatment during the initial two-week run-in phase. Of the 189 patients who responded to BUP, 15.8% discontinued the study: 7 in the BUP TDS group and 24 in the placebo group.
• Of patients in the BUP TDS group, 74% responded to the treatment, compared to 50% in the placebo group (p = 0.0003).
• The most commonly reported adverse events were nausea, vomiting, and constipation.
• Compared to patients receiving placebo, patients receiving BUP TDS had a greater degree of global satisfaction, reported lower pain scores, and used less rescue medication.

Findings suggest that, for some patients, transdermal buprenorphine may be effective in the treatment of chronic cancer pain.

• There was a substantial dropout rate after the two-week initial study.
• To be eligible for the study, all patients had to have chronic severe pain. It is not at all surprising that patients using any pain medication would respond better than patients receiving placebo.
• Authors note that European Medicines Agency guidelines regarding chronic pain recommend comparing active treatment versus placebo to prove efficacy. However, this procedure raises concerns about the relevance of such comparisons and resulting findings to actual clinical care.
• Patients entered into the placebo-controlled part of this study were only those who clearly demonstrated response to BUP TDS. Results indicated that more than 30% of initial patients did not meet this criteria and did not respond to BUP TDS.

Transdermal buprenorphine may be helpful to some patients, but in this study more than one-third of cases did not respond to the treatment. The relevance of the findings of a placebo-controlled trial such as this one are questionable; patients with chronic pain would be expected to respond better to any pain medication than to placebo. Authors provide no information about the value of transdermal buprenorphine compared to the value of other analgesics.